Numerous infertile patients undergo ovulation induction procedures every year. Up until two decades ago ovulation induction was used solely for the treatment of anovulatory infertility; however, the introduction of assisted reproduction technology (ART) has expanded the use of these procedures to eumenorrheic women, with the goal of achieving multiple folliculogenesis.
For assisted reproduction techniques (ART), such as in vitro fertilisation (IVF) or IVF in conjunction with intracytoplasmic sperm injection (IVF/ICSI) and embryo transfer (ET), oocytes are collected from a female patient immediately prior to ovulation. The oocytes are fertilised in vitro, the resulting embryos are evaluated, and selected for implantation. Fertilisation will not occur for every oocyte, and not every fertilised oocyte will develop into a viable embryo. Furthermore, implantation may fail to occur. Because of the many possibilities for an unsuccessful outcome, and the relatively invasive nature of oocyte collection, it is desirable to maximise the number of oocytes collected.
For this reason, ART is typically carried out using controlled ovarian hyperstimulation (COH) to increase the number of oocytes1. Standard regimens2 for COH include a down-regulation phase in which endogenous luteinising hormone (LH) is down-regulated by administration of a gonadotropin releasing hormone (GnRH) agonist followed by a stimulatory phase in which follicular development (folliculogenesis) is induced by daily administration of follicle stimulating hormone (FSH), usually at about 150-225 IU/day. Other molecules having FSH activity may also be used. Alternatively stimulation is started with FSH after spontaneous or induced menstruation, followed by administration of a GnRH-antagonist (typically starting around day six of the stimulatory phase). When there are at least 3 follicles>16 mm (one of 18 mm), a single bolus of hCG (5-10,000 IU) is given to mimic the natural LH surge and trigger ovulation. Oocyte recovery is timed for 36-38 hours after the hCG injection.
The rationale for the use of GnRH analogues, e.g. agonists or antagonists, in this context is the prevention of an untimely LH surge which can cause premature ovulation and follicle luteinisation3. It has consistently been found that long GnRH agonist regimens (i.e., those started in the midluteal phase of the cycle preceding ovulation induction, or before) are associated with easier patient scheduling, greater follicle yield, and overall better clinical results.4 The use of antagonists is relatively new to the clinic, but it is expected to yield similar benefits, with the advantage of a shorter dosing period.
The prolonged administration of GnRH agonists or the administration of GnRH antagonists results in profound suppression of endogenous LH throughout the cycle, in the case of an agonist, or late in the stimulatory phase, with an antagonist. This situation, while not incompatible with follicle development, does not mimic the natural cycle. In the natural cycle, LH levels show a gradual increase several days before the large peak at midcycle.
Many groups have investigated the importance of LH during the stimulatory phase of COH and ovulation induction regimens. As is well known and recognised in the art, techniques or methods of ovulation induction (OI) are distinct from methods of COH, although both may involve the administration of FSH.
Filicori et al. has investigated the role of low doses of hCG, as a surrogate for LH, in folliculogenesis and ovulation induction5. hCG was given (50 IU hCG/day), starting synchronously with FSH administration. This regimen was continued on a daily basis until ovulation was triggered with a bolus of hCG. The numbers of small (<10 mm), medium (10-14 mm) and large (>14 mm) follicles were comparable between a group receiving hCG and a control group receiving FSH alone, however, the cumulative dose of FSH and the duration of FSH stimulation were reduced in the hCG treated group.
WO 00/67778 (Applied Research Systems) proposes the use of LH during the stimulatory phase. In one study, patients were administered FSH and LH in the early stimulatory phase, and then either both FSH and LH or just LH during the late stimulatory phase. In another study, patients were administered FSH alone in the early stimulatory phase and then LH in the late stimulatory phase. It was suggested that LH in the late stimulatory phase is responsible for atresia of non-dominant follicles. The regimen is proposed to encourage the development of a single dominant follicle.
The administration of rhLH (75 and 225 IU/day) for supporting rhFSH-induced follicular development in hypogonadotrophic hypogonadal women is reported by the European Recombinant Human LH Study Group to promote estradiol secretion, enhance the effect of FSH on follicular growth, and permit the successful luteinisation of follicles when exposed to hCG, as compared to a regimen of FSH alone6. The LH was administered starting on the same day as FSH stimulation, and was continued until hCG administration to trigger ovulation.
Sullivan et al. report that LH late in the stimulatory phase sustains follicular estradiol production when FSH is withdrawn7.
Sills et al. report a study in which patients suffering from infertility of various types were treated with either FSH or FSH and 75 IU rhLH throughout the stimulatory phase. The authors conclude that the addition of exogenous LH throughout ovulation induction does not materially alter cycle performance8.
Ben-Amor et al.9 and Werlin et al.10 have examined the effect of administering rhLH during the second half of the follicular phase in normally ovulatory patients with a long down regulation regimen, and Williams et al.11 have studied the effect of administering different doses of r-hLH during the whole FSH stimulation. No substantial clinical benefits were reported in these patient groups.
In COH regimens using FSH, some patients (“poor responders”) fail to respond to the initial doses of FSH, and the treatment cycle may be abandoned, and a new cycle started with a higher initial dose of FSH. Other groups of patients require repeated cycles because they fail to become pregnant even though oocyte recovery is successful. If repeat cycles are necessary, there may be adverse physical and emotional effects on the patient. Each repeat cycle entails a tremendous disruption in the life of the infertile couple.
It would be desirable to have a method that would permit the same or improved follicular response to COH using decreased FSH doses or decreased dosing periods. It would also be desirable to have a diagnostic test which could determine which patients may be poor or sub-optimal responders, and which patients may respond on a decreased FSH dose.